About 30% of drugs that appear on the World Health Organization (WHO) Essential Drug List were reported to be poorly water-soluble, based on the Biopharmaceutics Classification System (BCS). See, for example, Kasim, N. A., et al., Molecular properties of WHO essential drugs and provisional biopharmaceutical classification, Molecular Pharmaceutics 2004, 1(1): p. 85-96. Over 40% of newly developed pharmaceutically active substances have solubility issues (Lipinski, C. A., Drug-like properties and the causes of poor solubility and poor permeability, Journal of Pharmacological and Toxicological Methods 2000, 44(1): p. 235-249). The poor dissolution and/or permeability of these drugs often result in low and highly variable bioavailability. An obstacle in commercializing these compounds can be the difficulty of enhancing the extent of dissolution and dissolution rate of the active pharmaceutical ingredient.
Lenalidomide (Revlimid®) is approved in the United States as an oral treatment for multiple myeloma in combination with dexamethasone in patients who have received at least one prior therapy, transfusion-dependent anemia due to certain myelodysplastic syndromes, and relapsed mantle cell lymphoma. Though lenalidomide is soluble in organic solvents and in acidic solutions, its solubility is significantly reduced at pH closer to 7, ranging from 0.4 to 0.5 mg/mL (Revlimid® Full Prescribing Information, June 2013, Celgene Corporation, Section 11).
Pomalidomide (Pomalyst®) is approved in the United States as an oral treatment for multiple myeloma progressing in patients who have received at least two prior therapies. The solubility of pomalidomide is low, about 0.01 mg/mL, regardless of pH (Pomalyst® Full Prescribing Information, February 2013, Celgene Corporation, Section 11).
Additionally, pomalidomide is a substrate of the CYP1A2 and CYP3A liver enzymes, which can lead to adverse drug-drug interactions with other therapies that may be taken that inhibit and/or induce one or both enzymes (Pomalyst® Full Prescribing Information, February 2013, Celgene Corporation, Section 7).
While their insolubility allows for their preparation in capsule form for oral dosing, lenalidomide and pomalidomide are precluded from intravenous (IV) administration used in other treatments for, e.g., multiple myeloma, such as bisphosphonate therapy. The development of soluble lenalidomide and pomalidomide derivatives would allow for IV dosing, which can alleviate some of the aforementioned problems.
Accordingly, there is a clear and continuing need to create more soluble forms of lenalidomide and pomalidomide.